Medicine:Exercise-induced anaphylaxis

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Short description: Severe allergic reaction due to physical activity

Exercise-induced anaphylaxis (EIA, EIAn, EIAs) is a rare condition in which anaphylaxis, a serious or life-threatening allergic response, is brought on by physical activity.[1] Approximately 5–15% of all reported cases of anaphylaxis are thought to be exercise-induced.[2]

The exact proportion of the population with EIA is unknown, but a 2001 study of 76,229 Japanese junior high students showed that the frequency of EIA was 0.031%.[3]

Exercise-induced anaphylaxis is not a widely known or understood condition, with the first research on the disorder only having been conducted in the past 40 years. A case report in 1979 on EIA was the first research of its kind, where a patient was described to experience anaphylactic shock related to exercise 5–24 hours following the consumption of shellfish.[4]

The condition is thought to be more prevalent in women, with two studies of EIA patients reporting a ratio of 2:1 for females:males with the disorder.[5][6] There is, however, thought to be no link to ethnicity.[7]

Survey results from EIA patients have shown that the average number of attacks per year is 14.5.[6] However, most sufferers of EIA report that both severity and frequency of attacks decrease over time.[8]

Symptoms

The anaphylaxis campaign splits symptoms of EIA into two categories: mild and severe. Mild symptoms may include "widespread flushing of the skin", hives or urticaria, swelling of the body (angioedema), swelling of the lips, and nausea or vomiting.[9] More severe symptoms might include the swelling of the tongue, difficulty in swallowing or breathing, constriction of the airways, feeling faint, and unconsciousness.[9]

Symptoms can start immediately following exercise, but 90% of patients report experiencing an attack 30 minutes following activity.[6]

Figure 1; a table by Barg et al. showing the frequency of different EIA symptoms in two different studies.[7]
Frequency of EIA symptoms in studied population (%)
Symptom Wade et al.[5] Shadick et al.[6]
Itching 92 92
Urticaria 83 86
Angioedema 78 72
Flushing 75 70
Shortness of breath 59 51
Dysphagia - 34
Chest tightness - 33
Loss of consciousness 32 32
Diaphoresis 43 32
Headache 30 28
Nausea/diarrhoea/colic 30 28
Throat constriction - 25

A paper by Sheffer and Austen (1980) splits an EIA event into four distinct stages: prodromal, early, fully developed, and late.[10] Characteristic symptoms of the prodromal stage include redness and itching. In the early stage, generalised urticaria develops. If the reaction does not diminish, it may become fully developed EIA, in which gastrointestinal symptoms and constriction of the airway may occur. The late phase, which follows recovery from the reaction, includes frontal headaches and a feeling of fatigue; these symptoms may manifest themselves up to 72 hours following onset of the reaction.[10]

Cardiovascular symptoms are reported in 1/3 of patients diagnosed with EIA.[6]

Food-dependent exercise-induced anaphylaxis

Food-dependent exercise-induced anaphylaxis (FDEIA) is a subcategory of the disorder where exercise only invokes a reaction when followed by the ingestion of a food allergen. Patients whose EIA is food-dependent are thought to make up from one third to a half of all EIA cases.[7] In a 2001 study of 76,229 Japanese junior high students, 0.017% of students were found to suffer from the condition.[3]

In European countries, the most common trigger foods for FDEIA are tomatoes, cereals and peanuts.[11] In Japan, FDEIA is most commonly triggered by omega-5-gliadins, an allergen found in wheat.[12][13] Other common foods thought to be linked to FDEIA include shellfish, seeds, dairy (in particular cow's milk), fruits and vegetables (such as grapes, onions and oranges), meats, and even mushrooms.[2]

Ingestion of the trigger food most often precedes exercise by minutes or hours in cases of an attack; there are, however, reported incidents of attacks occurring when ingestion transpires shortly following activity.[7] While a lot remains unknown about the pathophysiology of food-dependent exercise-induced anaphylaxis (FDEIA), one theory points to changes in pH; this theory is based on the fact that pH becomes more acidic in the muscles and serum following exercise. Decreasing pH is associated with an increase in mast cell degranulation, a key component to the immune response, and one study found that, when patients with FDEIA are given the antacid sodium bicarbonate prior to exercise, they do not experience FDEIA symptoms.[14]

Common triggers

Exercise-induced anaphylaxis is most commonly brought on by aerobic exercise. It is most often caused by higher levels of exertion, such as jogging, but can be brought on by milder activities, such as a gentle walk.[15] In a 1999 study, 78% of sufferers reported that attacks were frequently caused by jogging, whereas 42% reported symptoms following brisk walking.[6]

There are several factors outside of food and exercise that have been suggested to increase the risk of an EIA attack. These include the consumption of alcohol, exposure to pollen, extreme temperatures, the taking of non-steroidal anti-inflammatory drugs (NSAIDs), and even certain phases of the menstrual cycle.[16]

Pathophysiology

The pathophysiology surrounding EIA and FDEIA is not yet fully understood, but there are several theories.

Research shows that histamine, a chemical involved in the allergic response, plays a key role in EIA. Increased histamine levels in the blood plasma have been recorded during incidents of both EIA[17][18] and FDEIA.[3] Morphological changes in mast cells in the skin of EIA patients have been observed following exercise, and are comparable to changes occurring in atopic patients following exposure to an allergen.[19]

Theories for the pathophysiology of EIA include increased gastrointestinal permeability, increased tissue enzyme activity, and blood flow redistribution.

Gastrointestinal permeability

Exercise is known to increase absorption from the gastrointestinal tract.[7] It is theorised that increased or altered gastrointestinal permeability enhances contact of allergens with the gut-associated immune system.[7] In some FDEIA patients, the appearance and/or severity of symptoms depends on the amount of the patient's trigger food ingested.[20] An increase in gut permeability may also increase the risk of absorption of 'partially digested allergenic proteins'.[7] Supporting research for this theory includes a study by Matsuo et al. (2005), where wheat-dependent EIA sufferers were found to have omega-5-gliadins in their sera following exercise and consumption of wheat, but not in patients that ingested wheat only.[21]

Increased tissue enzymatic activity

Another theory is that exercise and aspirin could activate tissue transglutaminase in intestinal mucus.[7] Omega-5-gliadins, a compound found in wheat that is commonly associated with FDEIA, is cross-linked by transglutaminase, resulting in large formations of peptide aggregates, and leads to an increase in IgE binding.[22]

Blood flow redistribution

During exercise, blood is redistributed from inactive to active tissues in the body.[7] It has been suggested that food-sensitised immune cells associated with the gut do not evoke anaphylactic symptoms so long as they remain in a local circulation.[23] The theory suggests that if these sensitised cells are shifted to the skin and/or skeletal muscles following exercise, FDEIA symptoms are likely to occur.[23] A 2010 study demonstrated that food allergens were well tolerated by mast cells in the intestinal tract, and thus no symptoms occurred at rest.[24] Mast cells are structurally different in the gut than those found in the skin or skeletal muscles,[25] and thus could be induced by food allergens.

Treatment

If exercise is stopped when symptoms are first detected, improvement in condition normally occurs within minutes, and no further treatment is required.[15][16]

Common treatments for the condition include taking regular anti-histamines, the use of an epinephrine injector (commonly known as an EpiPen), and through abstinence of exercise. In a 1999 study, 56% of sufferers reported the use of anti-histamines as treatment for their EIA, and 31% reported having treated the condition with epinephrine.[6] Many patients reported treating the condition with changes in behaviour, with 44% of EIA sufferers reporting having reduced the incidence of attacks by avoiding exercise during "extremely hot or cold weather", 37% by avoiding trigger foods, 36% by refraining from exercise during allergy season, and 33% during high humidity.[6]

References

[26][9]

  1. ↑ "Exercise-Induced Anaphylaxis (EIA)". Golisano Children's Hospital – University of Rochester Medical Center. https://www.urmc.rochester.edu/childrens-hospital/allergy/exercise-induced-anaphylaxis-eia.aspx. 
  2. ↑ 2.0 2.1 "Food-dependent exercise-induced anaphylaxis in childhood". Pediatric Allergy and Immunology 18 (5): 455–63. August 2007. doi:10.1111/j.1399-3038.2007.00599.x. PMID 17617816. 
  3. ↑ 3.0 3.1 3.2 "Frequency of food-dependent, exercise-induced anaphylaxis in Japanese junior-high-school students". The Journal of Allergy and Clinical Immunology 108 (6): 1035–9. December 2001. doi:10.1067/mai.2001.119914. PMID 11742285. 
  4. ↑ "Exercise-induced anaphylactic reaction to shellfish". The Journal of Allergy and Clinical Immunology 63 (6): 433–4. June 1979. doi:10.1016/0091-6749(79)90218-5. PMID 447945. 
  5. ↑ 5.0 5.1 "Exercise-induced anaphylaxis: epidemiologic observations". Progress in Clinical and Biological Research 297: 175–82. 1989. PMID 2587584. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 "The natural history of exercise-induced anaphylaxis: survey results from a 10-year follow-up study". The Journal of Allergy and Clinical Immunology 104 (1): 123–7. July 1999. doi:10.1016/s0091-6749(99)70123-5. PMID 10400849. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 "Exercise-induced anaphylaxis: an update on diagnosis and treatment". Current Allergy and Asthma Reports 11 (1): 45–51. February 2011. doi:10.1007/s11882-010-0150-y. PMID 20922508. 
  8. ↑ "Exercise-induced anaphylaxis". Genetic and Rare Diseases Information Center. https://rarediseases.info.nih.gov/diseases/6392/exercise-induced-anaphylaxis#ref_12355. 
  9. ↑ 9.0 9.1 9.2 "Anaphylaxis Campaign". https://www.anaphylaxis.org.uk/. 
  10. ↑ 10.0 10.1 "Exercise-induced anaphylaxis". The Journal of Allergy and Clinical Immunology 66 (2): 106–11. August 1980. doi:10.1016/0091-6749(80)90056-1. PMID 7400473. 
  11. ↑ "Food-dependent exercise-induced anaphylaxis: clinical and laboratory findings in 54 subjects". International Archives of Allergy and Immunology 125 (3): 264–72. July 2001. doi:10.1159/000053825. PMID 11490160. 
  12. ↑ "Food-dependent exercise-induced anaphylaxis". Journal of Dermatological Science 47 (2): 109–17. August 2007. doi:10.1016/j.jdermsci.2007.03.004. PMID 17507204. 
  13. ↑ "Food-dependent exercise-induced anaphylaxis -importance of omega-5 gliadin and HMW-glutenin as causative antigens for wheat-dependent exercise-induced anaphylaxis-". Allergology International 58 (4): 493–8. December 2009. doi:10.2332/allergolint.09-RAI-0125. PMID 19847096. 
  14. ↑ "Exercise-induced anaphylaxis: A clinical view". Italian Journal of Pediatrics 38 (1): 43. September 2012. doi:10.1186/1824-7288-38-43. PMID 22980517. 
  15. ↑ 15.0 15.1 Exercise-Induced Anaphylaxis: Background, Pathophysiology, Epidemiology. 2017-11-20. https://emedicine.medscape.com/article/886641-overview. Retrieved 2018-09-22. 
  16. ↑ 16.0 16.1 "Exercise-induced anaphylaxis". Immunology and Allergy Clinics of North America 35 (2): 261–75. May 2015. doi:10.1016/j.iac.2015.01.005. PMID 25841550. 
  17. ↑ "Exercise-induced urticaria, angioedema, and anaphylactoid episodes". The Journal of Allergy and Clinical Immunology 68 (6): 432–7. December 1981. doi:10.1016/0091-6749(81)90197-4. PMID 7310010. 
  18. ↑ "Exercise-induced anaphylaxis: a distinct form of physical allergy". The Journal of Allergy and Clinical Immunology 71 (3): 311–6. March 1983. doi:10.1016/0091-6749(83)90085-4. PMID 6826991. 
  19. ↑ "Exercise-induced anaphylaxis: a serious form of physical allergy associated with mast cell degranulation". The Journal of Allergy and Clinical Immunology 75 (4): 479–84. April 1985. doi:10.1016/s0091-6749(85)80021-x. PMID 3980883. 
  20. ↑ "Food-dependent exercise-induced anaphylaxis: a case related to the amount of food allergen ingested". The British Journal of Dermatology 138 (5): 898–900. May 1998. doi:10.1046/j.1365-2133.1998.02254.x. PMID 9666843. 
  21. ↑ "Exercise and aspirin increase levels of circulating gliadin peptides in patients with wheat-dependent exercise-induced anaphylaxis". Clinical and Experimental Allergy 35 (4): 461–6. April 2005. doi:10.1111/j.1365-2222.2005.02213.x. PMID 15836754. 
  22. ↑ "Transglutaminase-mediated cross-linking of a peptic fraction of omega-5 gliadin enhances IgE reactivity in wheat-dependent, exercise-induced anaphylaxis". The Journal of Allergy and Clinical Immunology 111 (6): 1386–92. June 2003. doi:10.1067/mai.2003.1498. PMID 12789243. 
  23. ↑ 23.0 23.1 "Dangerous exercise: lessons learned from dysregulated inflammatory responses to physical activity". Journal of Applied Physiology 103 (2): 700–9. August 2007. doi:10.1152/japplphysiol.00225.2007. PMID 17495117. https://escholarship.org/content/qt5gh9q1vt/qt5gh9q1vt.pdf?t=pqczy9. 
  24. ↑ "Pathophysiology, diagnosis and management of exercise-induced anaphylaxis". Current Opinion in Allergy and Clinical Immunology 10 (4): 312–7. August 2010. doi:10.1097/ACI.0b013e32833b9bb0. PMID 20543674. 
  25. ↑ "Development, significance, and heterogeneity of mast cells with particular regard to the mast cell-specific proteases chymase and tryptase". Journal of Leukocyte Biology 61 (3): 233–45. March 1997. doi:10.1002/jlb.61.3.233. PMID 9060446. 
  26. ↑ "Exercise-induced anaphylaxis: an update on diagnosis and treatment". Current Allergy and Asthma Reports 11 (1): 45–51. February 2011. doi:10.1007/s11882-010-0150-y. PMID 20922508. 



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